Project Summary/Abstract In the earliest stages of Alzheimer?s disease (AD), hyperphosphorylated and conformationally abnormal (pathological) tau in the form of tangles, and selective neuronal loss have been found in the superficial layers of the entorhinal cortex and in the CA1 of hippocampus. However, the precise neuronal cell types that accumulate tangles and the biochemical pathways mediating this selective neuronal vulnerability are not known. We, and others, have found that excitatory neurons in the EC and CA1 of hippocampus are particularly vulnerable to tau pathology. Notably, Wolfram Syndrome 1 (WFS1), a transmembrane glycoprotein localized to the endoplasmic reticulum (ER), is differentially expressed in excitatory neurons in those two regions. WFS1 dysfunction has been found to contribute to neurodegeneration as well as stress and depression, possibly by regulating the endoplasmic reticulum (ER) stress and/or the hypothalamic?pituitary?adrenal (HPA) axis. Based on these observations, I hypothesize that tau pathology will reduce the expression of WFS1, resulting in ER and cytosolic calcium dyshomeostasis, persistent activation of ER stress pathways and other as yet unknown pathways, which in turn will exacerbate tau pathology, synaptic dysfunction, neuronal loss and cognitive deficits. To test this hypothesis, this proposal will (1) determine if WFS1-expressing excitatory neurons in the superficial layers of medial entorhinal cortex (MEC) and in the CA1 of hippocampus are vulnerable to tau pathology in tau transgenic mice and in human AD; (2) investigate whether overexpression of WFS1 ameliorates ER calcium dyshomeostasis, ER stress, tau pathology, glial activation, synaptic dysfunction and cognitive deficits in rTg4510 tau mice; (3) explore whether conditional knockout of WFS1 in the brain exacerbates ER calcium dyshomeostasis, ER stress, tau pathology, glial activation, synaptic dysfunction and cognitive deficits in rTg4510 tau mice; and (4) define the interaction between WFS1 and tau, and biochemical pathways in addition to the ER stress pathways that underlie the vulnerability of WFS1-expressing excitatory neurons to tau pathology in tau transgenic mice and in human AD. Identifying the molecular mechanisms underlying pathological tau- mediated neuronal vulnerability and neurodegeneration in AD could aid in the discovery of novel drug targets that can be targeted to protect vulnerable neurons. In addition, the approaches proposed to characterize cell populations vulnerable to pathological proteins in AD can be applied to a wide range of degenerative diseases that also show selective, cellular vulnerability.